Tremor is defined as an involuntary, rhythmic oscillatory movement of a part or parts of the body, resulting from alternating or irregularly synchronous contractions of antagonist muscles. Tremor is the most common form of involuntary movement. Almost all individuals have experienced tremor at some point in their lives; however, only a small fraction of those with tremor seek medical attention. Tremors may result from normal (physiologic) or pathologic processes and may be characterized by their etiology or phenomenology (i.e., neuropathology, activation state, frequency, amplitude,). With the exception of those affecting the facial region, tremors are frequently defined or characterized by the joint around which the body part moves.
Tremor occurs when normal muscle activation is replaced by abnormal synchronous bursts. This evolves through alterations in ionic cell conductance in the cell membrane, causing the cell membrane to produce oscillation in its potential. The tendency to oscillate can be exaggerated by hyperpolarization of the cell away from the normal resting potential. Mainly, tremor is thought to be staged in the thalamic relay nuclei and inferior olive. The activity of neighboring cells can be coupled by electronic gap junctions in the olive and by recurrent axonal projections from the reticular nucleus in the thalamus. So, a large population of cells can oscillate together and exert a powerful rhythmic influence on motor output. Similarly, low-threshold calcium spike burst could be at the origin of rigidity and dystonia through the activation of the supplementary motor area and akinesia, when reaching the pre-supplementary motor area.
Individuals of all ages have tremor (physiological tremor) associated with anxiety, fatigue, anger, caffeine, pain, extreme cold, and other stressful situations. Excessive and persistent tremor is a neuro-pathologic phenomenon frequently associated with a neurological disorder called essential tremor. The National Institute of Neurological Disorders and Stroke estimates that as many as 10 million people in the United States are affected with essential tremor (ET). Essential tremor affects equally in females and males. Essential tremor may begin at any age, though it is unusual before the age of 20 years. Existing essential tremor often, though not always becomes worse with age, but may also make its initial appearance at an older age.
Pathologic tremor occurs when the normal continuous pattern of muscle activation is replaced by relatively synchronous neuronal bursting. This is characterized as an involuntary rhythmic oscillation of reciprocally innervated antagonistic muscle groups, causing movement of a body part about a fixed plane in space. Frequency of oscillation is divided into three main components: slow (3 to 5 Hz), intermediate (5 to 8 Hz), or rapid (9 to 12 Hz). The amplitude of oscillation is defined as fine, medium or coarse.
Current drug treatments of tremors do not offer long-term sustained efficacy and pose a high risk of complications with prolonged use. The most common and primarily prescribed treatment is a beta-blocker propranolol and its more potent, with longer half-life version, timolol. Many movement disorder specialists also choose to prescribe benzodiazapine (alprazolam, clonazepam, diazepam, lorazepam), anti-depressant (trazadone, mirtazapine), centrally acting alpha-agonist (clonidine), anti-apsamodic (botulinum toxin injection), anti-seizure (gabapentin, primidone, phenobarbital) type medications. It was recently reported that the noncompetitive NMDA channel blocker, MK-801 could block the tremorogenic actions of harmaline. Competitive blockade of harmaline-induced tremor by MK-801 occurs within the calcium channel coupled to the NMDA receptorA number of surgical treatments have become available to these tremors. These procedures, which involve stimulation or ablation of the thalamic region via surgical intervention, have a risk factor of aneurysm and death of about 2 to 3%. Thus, there is a clear need for an effective, low risk therapy for tremors.
Zonisamide is an antiseizure drug classified as a sulfonamide and chemically unrelated to other antiseizure agents. Zonisamide has the chemical structure of 1,2-benzisoxazole-3-methanesulfonamide and is further characterized in the Merck Index (11th Ed. 1989) at monograph no. 10094. Zonisamide and related structures are described in described in U.S. Pat. No. 4,172,896, which is hereby incorporated herein by reference in its entirety for all purposes. It is approved for use in humans in the United States, Korea and in Japan. The mechanism(s) by which zonisamide exerts its antiseizure activity is unknown. Anticonvulsant activity has been demonstrated by an increase in threshold for generalized seizures in the kindled rat model and by a reduction in the duration of cortical focal seizures induced by electrical stimulation of the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats.
Zonisamide may produce anti-epileptic and anti-convulsant effects through action at both sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks voltage-gated sodium channels and reduces voltage-dependent, transient inward calcium currents (T-type Ca2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion that does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10-30 μg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [3H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission.
Murata, et al., (Neurocsci Res. 41:397(2001)) report that patients given 50-200 mg/day zonisamide in addition to their anti-Parkinson Disease drug showed lessening of symptoms. Takigawa, et al., (Rinsho ShinKeigaKa, 37:1006-9 (1997)) report symptoms of cortical myoclonic tremor of one patient improved after treatment with zonisamide, clonazepam and valpolate. Taira (NoToShinKei 44:16-3 (1992)) reports that two patients developed resting and postural hand tremor after administration of zonisamide.
Based on the ability of zonisamide to suppress seizures generated in thalamic regions, Applicants have discovered that zonisamide is efficacious in treating tremors.